Medical use of protein drugs is constrained by three major drawbacks. The first is their short biological half-life which requires, in some cases, frequent administrations. The second is the rapid degradation which occurs in mucosal tissues that generally cover the body cavities. Lastly, most protein drugs are large molecules and therefore do not easily cross the intestinal epithelium. As a result, the bioavailability of orally administered protein-based drugs is typically extremely low. Therefore, the most common mode of protein drugs administration is the parenteral route. However, apart from the inconvenience to the patients, parenteral delivery systems are also more expensive in terms of production and drug administration. There is therefore an unmet medical need for an effective non-parenteral mode of administration of protein drugs that will provide protection against biological degradation and/or enhance its transport across mucosal barriers. Although sophisticated non-parenteral pharmaceutical systems, such as intra-nasal systems, have been developed, oral administration is more favorable, having the major advantage of convenience for increased patient compliance.
DNase, for example, is unstable in the presence of water, oxidative stress, temperature fluctuations, and acid pH conditions. The maximal activity is observed within a pH range of 6-8. These characteristics create difficulties for oral DNase administration. The only currently available methods of delivering active DNase to the plasma are via injection (IV, SC or IM). RNase can be deactivated by mutual interaction between different regions of the RNase molecule, and thus requires formulations capable of preventing this type of interaction.
Examples of biologically active proteins include but are not limited to growth factors, cytokines, peptide hormones, analgesic peptides, enzymes, blood coagulating factors, peptide neurotransmitters, antibodies and may include synthetic polymers of amino acids. Specific examples of biologically active proteins or peptides include pituitary growth hormone, erythropoietin, DNase, RNase, and monoclonal antibodies among others.
Biopolymers and Their Use in Delivering Active Agents
Biopolymers such as polysaccharides have been known for many years. Polysaccharides are widely used as excipients in oral dosage forms, as disclosed for example in U.S. Pat. No. 6,667,060 to Vandecruys and US patent application 2004/0115264 to Blouquin. These references neither disclose nor suggest use of biopolymers in combination with nanoparticles or oil.
Nanoparticles and Their Use in Delivering Active Agents
Silica nanoparticles are well known in the art as pharmaceutical excipients and are their use is disclosed for example in U.S. Pat. No. 6,322,765 to Muhlhofer and U.S. Pat. No. 6,698,247 to Tennent, among many others. Coating of a nanoparticle-biopolymer complex with oil, or utility of same in oral administration of active agents are neither disclosed nor suggested.
Methods for imparting a hydrophobic surface to nanoparticles are well known in the art and are described, for example in Chung et al (Hydrophobic modification of silica nanoparticle by using aerosol spray reactor. Colloids and Surfaces A: Physicochem. Eng. Aspects 236 (2004) 73-79). Additional methods include the reverse micelles method (Fu X, Qutubuddin S, Colloids Surf. A: Physicochem. Eng. Aspects 179: 65, 2001), liquid precipitation method (Krysztafkiewicz A, Jesionowski T, Binkowski S, Colloids Surf. A: Physicochem. Eng. Aspects 173:73, 2000) and sol-gel method (Jean J, Yang S, J. Am. Ceram. Soc. 83(8):1928, 2000; Zhang J, Gao L, Ceram. Int. 27: 143, 2001). Use of the nanoparticles in combination with biopolymers, coating a nanoparticles-biopolymer complex with oil, or utility of same in oral administration of active agents are neither disclosed nor suggested.
U.S. Pat. Nos. 7,105,229, 6,989,195, 6,482,517, 6,638,621, 6,458,387, 7,045,146, and 5,462,866 among many others disclose use of nanoparticles or microparticles as excipients for proteins. These references neither disclose nor suggest intimate non-covalent association of nanoparticles with a biopolymer or embedding of a nanoparticle-polymer matrix in an oil coating.
US 2007/0154559 to Pai discloses an orally administrable composition containing nanoparticles comprising a charged water-soluble drug in complex with a counter-ion substance, a lipid, a polymer, and an emulsifier. The compositions are formed by (a) ionically bonding the drug with the counter-ion; (b) adding a lipid, a polymer, and a solubilizing agent; dissolving the whole mixture; and introducing the solution into an aqueous solution containing an emulsifier; and (c) removing the solubilizing agent. US 2006/0177495 and 2003/0235619 to Allen disclose delivery vehicles for delivering an active agent, comprising nanoparticles composed of a biodegradable hydrophobic polymer forming a core and an outer amphiphilic layer surrounding the polymer core and containing a stabilizing lipid.
US 2006/0083781 to Shastri discloses nanoparticles comprising a lipid and a polymer comprising an ionic or ionizable moiety. These compositions as well differ significantly from those of the present invention, inter alia in that (a) the polymer is not outside the nanoparticles but rather forms a part of them; and (b) the oil forms a part of the nanoparticles instead of coating the nanoparticle-polymer mixture. In addition, the unique structure of the matrix carrier compositions of the present invention is neither disclosed nor suggested.
WO 96/37232 to Alonso Fernandez discloses methods for preparation of colloidal systems through the formation of ionic lipid-polysaccharide complexes. The colloidal systems are stabilized through the formation of an ionic complex, at the interface, comprised of a positively charged aminopolysaccharide and a negatively charged phospholipid. These compositions as well differ significantly from those of the present invention, inter alia in that (a) the polymer is not outside the nanoparticles but rather forms a part of them; and (b) the oil forms a part of the nanoparticles instead of coating them. In addition, the unique structure of the matrix carrier of the present invention is neither disclosed nor suggested.
U.S. Pat. No. 6,548,264 to Tan et al. discloses silica-coated nanoparticles and a process for producing silica-coated nanoparticles. Silica-coated nanoparticles are prepared by precipitating nano-sized cores from reagents dissolved in the aqueous compartment of a water-in-oil microemulsion. A reactive silicate is added to coat the cores with silica. The silicate coating may further be derivatized with a protein. US 2007/0275969 to Gurny discloses pharmaceutical compositions for the oral administration of pharmaceutical agents having low water solubility. The pharmaceutical agents are solubilized with a polymer, from which nanoparticles are formed.
In cosmetics formulations, it is common to use compositions comprising water-in-oil emulsions containing an aqueous phase dispersed in an oily phase. There are numerous examples in which silica nanoparticles as well as polysaccharides are included in the liquid fatty phase. U.S. Pat. No. 6,228,377 for example, discloses water-in-oil emulsions containing a liquid fatty phase which contains hydrophobic or hydrophilic fumed silica, a branched polysaccharide alkyl ether, an emulsifying surfactant and oil. These compositions differ significantly from those of the present invention in that they include a water phase and surfactants that serve as the most important structure forming factor of the composition.
Additional Strategies
Methods for oral administration of biologically active proteins and peptides are the object of extensive research efforts but have been proven generally inefficient to date. A number of strategies for preventing degradation of orally administered proteins have been suggested, including use of core-shell particles (U.S. Pat. No. 7,090,868 to Gower) and nano-tubes (U.S. Pat. No. 7,195,780 to Dennis). Liposomes have been used as a carrier for orally administered proteins, as well as aqueous emulsions and suspensions (U.S. Pat. No. 7,316,818; WO 06/062544; U.S. Pat. No. 6,071,535; and U.S. Pat. No. 5,874,105 to Watkins) and gas-filled liposomes (U.S. Pat. Nos. 6,551,576; 6,808,720; and 7,083,572 to Unger et al). Another composition comprises nanodroplets dispersed in an aqueous medium (US 2007/0184076). Additional strategies are found in WO 06/097793, WO 05/094785, and WO 03/066859 to Ben-Sason, which describe matrix-carriers containing peptide-effectors that provide penetration across biological barriers for administration of hydrophobic proteins; and EPO491114B1 to Guerrero Gomez-Pamo, which describes preparation of non-covalent protein-polysaccharide complexes for oral administration of biologically active substances, stabilized by precipitates of organic salts. None of these references discloses or suggests intimate non-covalent association of nanoparticles with a biopolymer or a nanoparticle-polymer matrix embedded in an oil coating.
In addition to the differences outlined above, none of the above references discloses or suggests the enhanced bioavailability of compositions of the present invention.